The goal of this Program Project Grant is to advance our knowledge of the neurobiological mechanisms that give rise to mental retardation and developmental disabilities, using clinically relevant animal model systems. The projects investigate pathophysiological responses at the cellular and molecular levels that are the consequences of genetic mutations and environmental agents. The projects focus on key mechanisms, such as anomalies in cell signaling, immune response, cytokines and cell death that generally contribute to the progression of neurodegenerative disorders. All projects propose to explore factors important in development, repair and regeneration in the CNS processes central to the problem of mental retardation. Project I will investigate the human arginase and arginase deficiency. Project II will investigate mechanisms of glial pathogenesis and regeneration in demyelinating diseases; Project II will investigate neurotrophic and cellular interactions in myelin repair; Project IV will investigate VIP and PACAP action in CNS development and injury. The investigators share: animal and injury models, cell culture systems, cell and molecular biology approaches and transgenic and mouse knockouts. This interactive and multi-disciplinary group uses tools from genetic manipulation to cell transplant to address biological processes. The long-term goal is to build the foundation for therapeutic strategies to restore neurobiological functions in impaired individuals. This program has recently attracted several outstanding and basic scientists. Have laboratories of the UCLA Mental retardation RESEARCH Center in four closely interrelated projects carry out the research effort. Each project draws on the expertise of investigators in the other components of the program project grant. The research effort of the five research teams is greatly facilitated by their close physical location, the sharing of an administrative and shared facilities and the access to excellent services and scientific cores in the UCLA Mental Retardation Research Center. This grant will facilitate the research training of pre- and post-doctoral fellows who wish to direct their career goals in research in mental retardation and developmental disabilities.